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MAJOR ARTICLE
African Tick Bite Fever in Travelers to Rural
Sub-Equatorial Africa
Mogens Jensenius,1 Pierre-Edouard Fournier,8 Sirkka Vene,7 Terje Hoel,2 Gunnar Hasle,4 Arne Z. Henriksen,5
Kjell Block Hellum,6 Didier Raoult,8 and Bjørn Myrvang,3 for the Norwegian African Tick Bite Fever Study Groupa
1
Department of Internal Medicine, Aker University Hospital, Departments of 2Preventive Medicine and 3Infectious Diseases, Ullevål University
Hospital, and 4Oslo Travel Clinic, Oslo; 5Department of Infectious Diseases, St. Olav’s University Hospital, Trondheim, and 6Department of
Infectious Diseases, Akershus University Hospital, Nordbyhagen, Norway; 7Swedish Institute for Infectious Disease Control, Solna, Sweden;
and 8Unité des Rickettsies, CNRS, UMR 6020 Université de la Mediterranee, Marseille, France
To estimate the incidence of, identify risk factors for, and describe the clinical presentation of travel-associated
African tick bite fever (ATBF), a rapidly emerging disease in travel medicine, we prospectively studied a cohort
of 940 travelers to rural sub-Equatorial Africa. Diagnosis was based on suicide polymerase chain reaction and
the detection of specific antibodies to Rickettia africae in serum samples by multiple-antigen microimmunofluorescence assay, Western blotting, and cross-adsorption assays. Thirty-eight travelers, 4.0% of the cohort
and 26.6% of those reporting flulike symptoms, had ATBF diagnosed. More than 80% of the patients had
fever, headache, and/or myalgia, whereas specific clinical features such as inoculation eschars, lymphadenitis,
cutaneous rash, and aphthous stomatitis were seen in ⭐50% of patients. Game hunting, travel to southern
Africa, and travel during November through April were found to be independent risk factors. Our study
suggests that ATBF is not uncommon in travelers to rural sub-Saharan Africa and that many cases have a
nonspecific presentation.
African tick bite fever (ATBF) is an acute, flulike illness
that is frequently accompanied by severe headache, inoculation eschars with regional lymphadenitis, vesicular
cutaneous rash, and aphthous stomatitis [1, 2]. ATBF
is caused by Rickettsia africae, a recently identified spotted fever group (SFG) rickettsia, and is transmitted in
rural sub-Saharan Africa by ungulate ticks of the Amblyomma genus, mainly Amblyomma hebraeum in
southern Africa and Amblyomma variegatum in West,
Received 18 December 2002; accepted 6 February 2003; electronically published
19 May 2003.
Financial support: Norwegian Research Council (grant 136239/320); Research
Forum, Aker University Hospital; Centre for Tropical and Imported Diseases, Ullevål
University Hospital, Oslo, Norway.
a
Members of the study group are listed at the end of the text.
Reprints or correspondence: Dr. Mogens Jensenius, Div. of Infectious Diseases,
Dept. of Internal Medicine, Aker University Hospital, N-0514 Oslo, Norway
([email protected]).
Clinical Infectious Diseases 2003; 36:1411–7
2003 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2003/3611-0009$15.00
central, and East Africa [3]. Recent surveys conducted
in areas of endemicity have yielded high prevalence
rates [4–6], and R. africae is now regarded as the most
widely distributed of all SFG rickettsiae known to be
pathogenic to humans [7].
Paralleled with the rapid expansion of safari tourism
to Africa during the past few years, ATBF has emerged
as a common cause of imported fever in many areas
where it is not endemic [1]. Most travelers are infected
in South Africa, Botswana, and Zimbabwe—countries
where many popular wildlife attractions at which R.
africae infection is highly endemic [8]. It is noteworthy,
and in contrast to other SFG rickettsioses, that most
cases of ATBF occur in clusters that can affect large
groups of exposed travelers, such as soldiers, leisure
safari tourists, game hunters, sports competitors, students, and foreign aid workers [1, 9–14].
So far, no prospective studies of ATBF have been
published, and many central epidemiological and clinical aspects of this disease still remain unclear. To es-
Travel-Associated African Tick Bite Fever • CID 2003:36 (1 June) • 1411
timate the incidence of, identify risk factors for, and describe
the spectrum of clinical manifestations in consecutive cases of
travel-associated ATBF, we prospectively studied a cohort of
Norwegian travelers to rural sub-Equatorial Africa.
MATERIALS AND METHODS
Nine travel-medicine clinics in Oslo, Akerhus, and SørTrønderlag counties, Norway, enrolled travelers in the study
from 1 January 1999 through 31 December 2000. Consecutive
attendees who planned to travel to rural areas in continental
sub-Equatorial Africa (including Kenya and Uganda) were
given oral and written information on ATBF and were asked
to participate in the study. Attendees who agreed to participate
were mailed a 2-page questionnaire on their return to Norway.
The questionnaire included queries about the country visited,
travel time frames, the purpose of travel, bush walking, limited
or no use of personal protection against arthropod bites (protective clothing, permethrine, and skin repellents), observed
tick bites or ticks on clothes or skin, the use of primitive accommodation (defined as an overnight stay outdoors, in a tent,
and/or in a straw hut), and the presence of any flulike symptoms (fever, myalgia, and headache) commencing no later than
10 days after leaving the rural area. Only travelers who submitted a completed questionnaire and reported travel to rural
areas were included in the study.
Travelers with flulike symptoms commencing no later than
10 days after leaving rural areas were also asked to present to
any of the study group’s infectious diseases specialists within
24 h. The medical evaluation included a physical examination
with special reference to inoculation eschars, regional lymphadenopathy, cutaneous rash and aphthous stomatitis, and blood
sampling for serological testing and PCR. Antirickettsial chemotherapy was administered to patients with fever. However,
the choice of agent, dosing, and duration and other diagnostic
procedures (including malaria blood smears, urine tests, and
radiography) were left to the subjective opinion of the physician
in charge. All patients with clinically suspected ATBF were offered a follow-up visit within 2–4 weeks for further medical
evaluation. The acute phase was defined as up to 14 days after
symptom onset, and the convalescent phase started on day 15.
Informed written consent was obtained from all participants
or their parents or guardians. The study protocol was reviewed
by the Regional Committee for Ethics and Research, Oslo,
Norway.
Microbiological diagnosis. The microbiological diagnosis
was based on the findings of suicide PCR and the detection of
specific antibodies to R. africae by multiple-antigen microimmunofluorescence (MIF), Western blot (WB), and cross-adsorption assay of serum samples. In general, the specificity of
1412 • CID 2003:36 (1 June) • Jensenius et al.
most serological tests for rickettsial infections is hampered by
extensive cross-reactions caused by immunogenic cell-wall lipopolysaccharide (LPS) antigens. Each of the serological methods that we used, however, has recently been found to have a
specificity of 100% in culture- and PCR-proven cases of ATBF
[1].
Suicide PCR was done as described elsewhere [1], using the
primer pairs AF1F-AF1R and AF2F-AF2R for 13 patients and
the 2 primer pairs polF1 (5-AAAGATATTGAATGTAACGG3)–polR1 (5-GAATATTAGTTCTAATATTCC-3) and polF2
(5-GACGAGATTTTACTATTAATGC-3)–polR2 (5-CTCGTGATAAAGTTTTTAAGCC-3), which were designed to amplify
a fragment of the pcnB gene encoding the poly (A) polymerase,
for the remaining patients. All positive PCR products were
identified by sequencing and comparison with R. africae ompA
(AF primers) or pcnB (pol primers) sequences. MIF was done
as reported elsewhere [11], using 7 SFG rickettsial antigens: R.
africae strain ESF-5, Rickettsia conorii strain 7 (Malish) ATCC
(American Type Culture Collection) VR-613T, Rickettsia mongolotimonae strain HA-91T, Rickettsia aeschlimannii strain
MC16T, Rickettsia massiliae strain Mtu1T, Rickettsia akari strain
MK ATCC VR-148T, and Rickettsia felis strain URRWXCal2.
WB procedures were done as described elsewhere [15], using
20 mL of a 1 mg/mL suspension of R. africae, R. conorii, or
Rickettsia aeschlimannii antigen per lane. Cross-adsorption for
serological testing was done as described elsewhere [16], using
R. africae and R. conorii antigens. All acute-phase serum samples were examined with suicide PCR, MIF, and WB, and all
convalescent-phase serum samples were tested with MIF and
WB. Serum samples from one-half of the patients for whom
PCR, MIF, and WB indicated SFG rickettsial infection but were
unable to identify the causative rickettsial species were randomly selected to undergo cross-adsorption assays.
In accordance with recently proposed criteria [1], we considered definite serological evidence of R. africae infection to
be (1) MIF titers of ⭓1:64 for IgG and/or ⭓1:32 for IgM, with
the IgG+IgM titers being at least 2 dilutions higher than any
of the other tested SFG rickettsial antigens; (2) a WB profile
that revealed only R. africae–specific antibodies; or (3) crossadsorption assays demonstrating that the homologous antibodies were directed against R. africae. For serological evidence
of recent nondeterminable SFG rickettsiosis, we accepted MIF
titers of IgG of ⭓1:64 and/or titers of IgM of ⭓1:32 that did
not fulfill the above criteria or a WB demonstrating antibodies
directed against high-molecular-weight surface proteins and
LPS antigens of 11 rickettsial species.
Case definitions. A case of confirmed ATBF was defined
as a flulike illness commencing no later than 10 days after the
patient left rural areas in sub-Equatorial Africa and with positive suicide PCR and/or definite serological evidence of R.
africae infection. A case of probable ATBF was defined as a
flulike illness commencing no later than 10 days after the patient left rural areas in sub-Equatorial Africa, with serological
evidence of recent nondeterminable SFG rickettsial infection,
and for which at least 1 of the patient’s fellow travelers had
similar symptoms and had confirmed ATBF diagnosed. A case
of nonspecific SFG rickettsiosis was defined as a flulike illness
commencing no later than 10 days after the patient left rural
areas in sub-Equatorial Africa, with serological evidence of recent nondeterminable SFG rickettsial infection, and for which
none of the patient’s fellow travelers had confirmed ATBF
diagnosed.
Statistical analyses. All data were analyzed using SPSS
software, version 11.0 (SPSS). For comparison of variables, we
used the x2 test, Fisher’s exact test, and Student’s t test of means,
when appropriate. The crude magnitude of the association between possible risk factors and seropositivity was measured with
ORs and 95% CIs. Variables included in the univariate logistic
regression model were age, male sex, travel to southern Africa
(South Africa, Swaziland, Lesotho, Namibia, and/or Botswana),
travel during the summer (November–April), a stay in rural
areas for 17 days, hunting as the purpose of travel, bush walk
with limited personal protection against arthropod bites, and
the use of primitive accommodations. Variables with a P value
of !.10 were entered into a multivariate logistic-regression
model. Observed differences were considered significant at
P ⭐ .05 for 2-tailed tests.
RESULTS
A total of 1153 attendees were requested to participate in the
study; of these, 1133 (98.3%) accepted. However, 57 attendees
who had agreed to participate did not travel to rural areas, and
136 did not submit a completed questionnaire, leaving 940
travelers to rural sub-Equatorial Africa to be included in the
study.
Among included travelers, there were 476 female (50.6%)
and 464 male (49.4%) travelers, with a mean age of 37.0 years
(median, 33 years; range, 4–86 years). There were 710 firsttime travelers (75.5%) to rural sub-Saharan Africa. The main
purposes of travel were leisure safari (44.7%), backpacking
(23.1%), business (12.1%), visiting friends and relatives
(11.0%), and game hunting (8.4%). There were 99 travelers
(10.5%) who visited rural areas in 11 country. The 5 most
common destinations were Kenya (26.5%), South Africa
(25.8%), Tanzania (23.9%), Zimbabwe (7.1%), and Botswana
(6.3%). Of the 420 people (44.7%) who travelled during the
summer, April was the most popular month (15.2%). The mean
length of stay in rural areas was 6.4 days (median, 5 days; range,
1–60 days), corresponding to a total time of 6016 person-days
(∼200 person-travel-months); only 5 travelers (0.5%) stayed
for 130 days in rural areas. Eighty-eight travelers (9.4%) used
primitive accommodations in rural areas. Bush walk was reported by 511 travelers (54.4%), and, of these, 312 (61.1%)
reported no or only limited use of personal protection against
arthropod bites.
Of the 940 travelers, 143 (15.2%) reported flulike symptoms;
of these, 83 presented for medical evaluation. Thirty-eight travelers (4.0% of the cohort and 26.6% of those reporting flulike
symptoms) had ATBF diagnosed (27 with confirmed ATBF and
11 with probable ATBF). In addition, 12 travelers had nonspecific SFG rickettsiosis diagnosed, resulting in an overall incidence of SFG rickettsiosis of 5.3%, corresponding to 0.25
cases per person-travel-month.
Of the 38 patients with ATBF, 23 (61%) were first-time travelers to rural sub-Saharan Africa. The incidences of ATBF varied
substantially among various groups of travelers: 20 (25.3%) of
79 for hunters, 3 (2.8%) of 107 for business travelers, 3 (2.6%)
of 114 for visitors to friends and relatives, 9 (2.1%) of 420 for
leisure travelers, and 3 (1.4%) of 218 in backpackers. In 15
(56%) of 27 confirmed ATBF cases, the infections occurred in
clusters. Tick bites or ticks on clothes or skin were observed
by 16 (48%) of 33 of patients with ATBF. After adjustment for
the confounding effects of male sex, travel duration 17 days,
the use of primitive accommodations, and bush walk with limited personal protection against arthropod bites, 3 factors were
significantly associated with ATBF in a multiple logistic regression model: hunting as the purpose of travel, travel to
southern Africa, and travel during the summer (table 1).
A selection of clinical characteristics of the patients with
ATBF is presented in table 2. Most patients had myalgia, headache, and fever, whereas inoculation eschars and regional lymphadenitis were present in ∼50% (figure 1). Multiple inoculation eschars (figure 2), ranging in number from 2 to 10, were
observed in 21% of the patients. Of the patients who reported
myalgia, virtually all complained about prominent neck muscle
pain and stiffness. Fifteen patients (39%) were treated with
antirickettsial treatment—13 were treated with doxycycline and
2 were treated with ciprofloxacin. Except for 1 patient who had
a fever for another 5 days, all treated febrile patients defervesced
within 48 h after the administration of antirickettsial therapy.
Two (5%) of 38 patients were briefly hospitalized.
A complicated course was documented in 1 case: a 44-yearold HLA B27 antigen–negative woman developed a painful
swelling in her right sternoclavicular joint 5 days after the onset
of ATBF symptoms and 3 days after the administration of doxycycline treatment. No joint puncture was performed, but a
diagnosis of reactive arthritis was made on clinical grounds.
The patient’s symptoms resolved with receipt of ciprofloxacin
(500 mg b.i.d. for 3 weeks).
Travel-Associated African Tick Bite Fever • CID 2003:36 (1 June) • 1413
Table 1. Findings of univariate and multivariate analyses of factors associated with African tick bite fever (ABTF) in 940 travelers
to rural sub-Equatorial Africa.
Patients
with ATBF
(n p 38)
Value
(%)
Variable
No. of
travelersa
Patients
without ATBF
(n p 902)
Value
(%)
OR (95% CI)
P
OR (95% CI)
P
889
—
.54
—
—
.34
38.3
38
Male sex
26 (68)
38
438 (49)
902
2.30 (1.44–4.61)
Travel to southern Africac
28 (74)
38
324 (36)
900
4.98 (2.39–10.38)
27 (71)
38
388 (43)
901
Travel duration of 17 days
18 (50)
36
197 (23)
Hunting as purpose of travel
20 (53)
38
9 (24)
37
19 (51)
37
301 (34)
d
Use of primitive accommodation
Bush walk with limited
personal protection
a
b
c
d
Multivariate
modelb
No. of
travelersa
Mean age, years
Travel during summer
36.9
Univariate
model
.016
0.63 (0.25–1.62)
!.001
3.06 (1.27–7.41)
.013
3.25 (1.59–6.62)
.001
2.80 (1.22–6.44)
.015
872
3.43 (1.75–6.71)
!.001
1.86 (0.82–4.20)
.13
59 (7)
900
15.84 (7.95–31.56)
!.001
10.18 (3.86–26.90)
!.001
332 (38)
868
0.52 (0.24–1.11)
.087
0.83 (0.33–2.11)
.70
877
2.02 (1.04–3.91)
.033
1.49 (0.69–3.24)
.31
No. of travelers for whom this information was available.
Done for variables with P ! .10 in the univariate model.
South Africa, Swaziland, Lesotho, Namibia, and/or Botswana.
November–April.
DISCUSSION
The story of travel-associated ATBF is an instructive one and
highlights the medical consequences of modern mass tourism
to the tropics. In fact, ATBF has now emerged from being a
practically unknown entity outside areas of endemicity only a
decade ago to be one of the more frequent causes of fever in
today’s travel medicine. The present study cohort, enrolled
through travel-medicine clinics and consisting of mostly shortterm and first-time safari tourists, is probably representative of
many, if not most, of today’s international travelers to rural
sub-Saharan Africa. Our data could therefore be of potential
interest to many health care providers, tour operators, and
presumptive travelers.
Table 2.
Clinical characteristics of 38
consecutive patients with travel-associated
African tick bite fever.
Characteristic
a
n/N (%)
Fever
29/36 (81)
Headache
30/36 (83)
Myalgia
33/38 (87)
Inoculation eschar
Single
Multiple
Regional lymphadenitis
12/38 (32)
8/38 (21)
18/37 (49)
Cutaneous rash
Musculopapular
Vesicular
Aphthous stomatitis
a
Temperature 137.5C.
1414 • CID 2003:36 (1 June) • Jensenius et al.
10/38 (26)
6/38 (16)
4/38 (11)
Epidemiology.
First, our estimated incidences of ATBF
(4.0%–5.3%) are notable and widely exceed those reported for
other tropical fevers in short-term travelers to tropical Africa,
including malaria, relapsing fever, African trypanosomiasis, and
typhoid fever [17, 18]. In fact, because only 58% of the travelers
who reported flulike symptoms presented for medical evaluation, the true incidence of ATBF might have been even higher
in the present cohort. Our estimates, which are consistent with
those of a recent seroepidemiological study of Norwegian firsttime travelers to rural sub-Equatorial Africa [19], could probably be largely explained by the unique features of the involved
tick vectors: Amblyommas are widely present on the vegetation
at many popular wildlife attractions in sub-Saharan Africa [8,
20–23], they are frequently (up to 70%) infected with R. africae
[24–26], and they are notoriously aggressive and readily bite
humans [27]. Second, those at highest risk for acquiring ATBF
in the present study were game hunters—travelers known to
be extensively exposed to ground vegetation and high grass, as
well as to ungulates and their hides [12, 28]. However, it is
important to recognize that other groups of travelers, such as
leisure safari tourists and business travelers, may also be infected, some during even brief visits to rural areas. Third, although R. africae infection appears to be widespread in most
parts of rural sub-Equatorial Africa, the risk of acquiring ATBF
in the present study varied significantly between travelers to
the 2 major safari destinations on the continent, southern and
East Africa. The reason for this geographical difference, which
is supported by most published case reports of travel-associated
ATBF [1], is unknown, but it may involve factors such as various strains of R. africae, varying transmission efficacy of the
2 principal vectors (A. hebraeum in southern Africa and A.
Figure 1.
A 30-year-old man with a single inoculation eschar on his buttock (black arrow) and regional lymphadenitis in his groin (white arrow)
variegatum in East Africa), or, possibly, various risk behaviors
among travelers. Fourth, although cases are encountered yearround, our data indicate that the risk of acquiring travelassociated ATBF is highest during the rainy summer, when tick
abundances peak in most areas of endemicity [21]. Last, with
56% of the cases being clustered, our data underscore that
Figure 2.
clusters are important epidemiological features of ATBF, as opposed to the other SFG rickettsioses endemic to sub-Saharan
Africa [1, 9–14].
Presentation. In contrast to previously reported cases [1,
9–13, 28–34], the full-blown clinical picture of ATBF was rarely
seen in our prospective series. Nonspecific flulike features dom-
A 50-year-old woman with multiple inoculation eschars on her thorax and neck (arrows)
Travel-Associated African Tick Bite Fever • CID 2003:36 (1 June) • 1415
inated the clinical presentations, and inoculation eschars, regional lymphadenitis, and vesicular rash, which are considered
to be the clinical hallmarks of ATBF, were seen in only ⭐50%
of the cases. Notably, multiple inoculation eschars, a pathognomonic feature of ATBF that is related to the unique aggressive behavior of the involved tick vectors, were documented
in only 21% of our cases, as opposed to 45% in a large retrospective series [1]. Of interest, prominent neck-muscle myalgia and nuchal stiffness, which have been reported elsewhere
in patients with Rocky Mountain spotted fever caused by Rickettsia rickettsii [35], were common in our series and may reflect
transient infection of the CNS. Aphthous stomatis has never
been documented in other SFG rickettsioses and seems to be
a distinct, albeit rare, clinical sign of ATBF [9, 32]. The underlying pathophysiological process is unknown but may include rickettsial infection of the oral mucosa, immunological
reactions, or both.
Only 41% of our patients were treated with antirickettsial
agents, a finding that contrasts that of a large retrospective series
in which 86% of patients with ATBF received such treatment
[1]. The status of chemotherapy for ATBF, including the choice
of agent, indications, and dosing, is uncertain and has never
been evaluated in clinical trials. However, as suggested by the
present data and several case reports [1, 9–13, 28–34], treatment
with tetracyclines, and possibly also with fluoroquinolones,
seems to be associated with the rapid clinical improvement in
most patients.
Prophylactic measures.
Many travelers to rural subSaharan Africa are not provided with any specific pretravel
information on ATBF or other tickborne diseases [19]. Such
information is obviously needed, at least in the high-risk setting.
Effective protection against tick bites during a stay in rural subSaharan Africa, however, may be difficult to accomplish. First,
the meticulous wearing of boots, pants, and long-sleeved shirts
may be considered too warm and inconvenient in tropical climates and was only done by a minority of the bush walkers
in our study. Second, tick larvae and nymphs, the 2 tick stages
that are most prone to bite humans, are minute and difficult
to spot [27]; typically, !50% of our patients with ATBF reported
to have observed ticks on themselves. Third, permethrin, a
synthetic pyrethroid and an effective acaricide for the treatment
of clothing [36], is not readily available in many countries
because of national regulations [37]. Fourth, the repellent efficacy of most insect skin repellents against the vectors of ATBF
is unknown but is likely to be short-lasting, as was demonstrated for 20% lotions of diethyl-toluamide and KBR 3023, a
recently developed piperidine compound [38]. Fifth, no vaccines are available for any SFG rickettsioses. Finally, although
it is a possible option for selected travelers at high risk, chemoprophylaxis with fluoroquinolones or tetracycline has never
1416 • CID 2003:36 (1 June) • Jensenius et al.
been evaluated in clinical trials and cannot currently be
recommended.
In conclusion, our data suggest that ATBF may be common
in short-term travelers to rural sub-Saharan Africa and that it
may cause a significant proportion of flulike illnesses in travelers to this region. Pretravel health care counsellors should
inform presumptive travelers about this risk, and, although
hard data are still lacking, hunters and other travelers at high
risk should be encouraged to take personal protective measures
against tick bites during bush walks in areas of endemic. Clinicians should be aware of the frequent nonspecific presentation of ATBF.
STUDY GROUP MEMBERS
Other members of the Norwegian African Tick Bite Fever Study
Group were Bjørg Bjotveit (Ski Medical Center, Ski), Arne
Brantsæter, (Bærum Hospital, Bærum), Helge Kjelshus (Fet
Medical Center, Fetsund), Bjørn Gillhagen (Volvat Medical
Center, Oslo), Herman Munthe-Kaas (Tåsen Medical Center,
Oslo), Mohammed Saeme (Christiania Travel Clinic, Oslo), and
Tor-Einar Vaage (Red Cross Medical Center, Oslo), Norway.
Acknowledgments
We are indebted to the following nurses for recruiting travelers to the study: Inger Eva Andersen, Frida Brandt-Burman,
Anne-Lise Bråten, Marie-Louise Engebretsen, Kristin Espe, Live
Grimseth, Brit Grimstad, Christin Hagen, Siri Jacobsen, Berthe
Lilleng, Inger Lilleøren, Ingrid Moum, Randi Oppheim, Mariann Ralmo, Kjersti Semelenge, Eva Skaug, Sissel Stråtveit, Eva
Karina Vethe, Liv Vinsand, and Annette Østnes.
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